N2 -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N 2  -alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of application Ser. No.671,436 Mar. 29, 1976, which in turn was a divisional of applicationSer. No. 622,390 filed Oct. 14, 1975 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N²-alkoxynaphthalenesulfonyl-L-argininamides and the pharmaceuticallyacceptable salts thereof, which are of especial value in view of theiroutstanding antithrombotic properties and low toxicities.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improvedagents for the treatment of thrombosis. The N²-(p-tolylsulfonyl)-L-arginine esters have been found to be one type ofagent which can be used and these have been found to be effective indissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971).

One family of compounds which have been found to be particularly usefulas highly specific inhibitors of thrombin for the control of thrombosisis the N² -dansyl-L-arginine ester or amide. (Our pending U.S.application Ser. No. 496,939, filed Aug. 13, 1974, now U.S. Pat. No.3,978,045).

However, there is a continuing need for a highly specific inhibitor onthrombin for the control of thrombosis, which exhibits lower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N²-alkoxynaphthalenesulfonyl-L-argininamides exhibit antithromboticactivity and even lower toxicity levels at the same relative potencies,as compared with the N² -dansyl-L-arginine ester or amide.

The compounds of this invention can be represented by the formula (I):##STR1## wherein R₁ is naphthyl substituted with at least one C₁ -C₅alkoxy; R₂ is selected from the group consisting of C₂ -C₁₀ alkyl, C₂-C₁₀ alkoxyalkyl, C₂ -C₁₀ alkylthioalkyl, C₇ -C₁₅ aralkyl, C₃ -C₁₀cycloalkyl and C₄ -C₁₀ cycloalkylalkyl; R₃ is C₁ -C₅ alkyl; and R₄ isselected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₇ -C₁₂aralkyl and C₆ -C₁₀ aryl.

Also encompassed within this invention are pharmaceutically acceptablesalts thereof.

This invention also relates to a method for inhibiting activity andsuppressing activation of thrombin in vivo, which comprises introducinginto a living body a pharmaceutically effective amount of an N²-alkoxynaphthalenesulfonyl-L-argininamide or the pharmaceuticallyacceptable salts thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N²-alkoxynaphthalenesulfonyl-L-argininamides of the formula (I): ##STR2##wherein R₁ is an alkoxynaphthyl wherein the alkoxy groups have 1-5(preferably 1-3) carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy or the like.Preferred are those naphthyl groups having one or two alkoxysubstituents, when two or more alkoxy groups are present, each may bethe same or different; R₂ is alkyl of 2-10 (preferably 2-6) carbonatoms, such as ethyl, propyl, butyl, isobutyl, pentyl, hexyl, octyl,decyl or the like, alkoxyalkyl of 2-10 (preferably 2-6) carbon atoms,such as methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl,2-ethoxyethyl, 2-propoxyethyl, 3-methoxypropyl, 3-ethoxypropyl,3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 4-butoxybutyl,5-butoxypentyl or the like, alkylthioalkyl of 2-10 (preferably 2-6)carbon atoms, such as methylthiomethyl, ethylthiomethyl,propylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl,2-propylthioethyl, 3-methylthiopropyl, 3-ethylthiopropyl,3-propylthiopropyl, 4-methylthiobutyl, 4-ethylthiobutyl,4-butylthiobutyl, 5-butylthiopentyl or the like, aralkyl of 7- 15(preferably 7-10) carbon atoms, such as benzyl, phenethyl,3-phenylpropyl, or the like; C₃ -C₁₀ cycloalkyl, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl or the like, or C₄ -C₁₀ cycloalkylalkyl, such ascyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclohexylethyl, cyclooctylmethyl or the like; R₃ is C₁ -C₅ alkyl,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,pentyl or the like; and R₄ is hydrogen, alkyl of 1-10 (preferably 1-6)carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl,octyl, decyl or the like, C₆ -C₁₀ aryl such as phenyl or naphthyl, andpreferably phenyl, or aralkyl of 7-12 (preferably 7-10) carbon atoms,such as benzyl, phenethyl or the like.

Suitable illustrations of R₁ in the above formula (I) are5-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl,4,6-dimethoxy-2-naphthyl, 7-methoxy-2-naphthyl,4,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl and 6,7-diethoxy-2-naphthyl.

Suitable R₂ groups in the above formula (I) are propyl, butyl, isobutyl,pentyl, hexyl, octyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl,2-methylthioethyl, 2-ethylthioethyl, 3-methylthiopropyl, benzyl,phenethyl, 3-phenylpropyl, cyclopropyl, cyclohexyl, cycloheptyl andcyclohexylmethyl.

Suitable R₃ group in the above formula (I) is methyl or isopropyl.

Suitable R₄ groups in the above formula (I) are hydrogen, ethyl andtert-butyl.

Illustrative of suitable N² -alkoxynaphthalenesulfonyl-L-argininamidesof sufficient activity of this invention are the following:

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylalaninetert-butyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-pentylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-pentylalaninetert-butyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalaninetert-butyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-phenethylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-phenethylalaninetert-butyl ester

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylalaninetert-butyl ester

N²-(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylmethylalanine

N²-(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylmethylalaninetert-butyl ester

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-propylalanine

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-propylalaninetert-butyl ester

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-2-methoxyethyl)anine

Of the compounds of this invention, it will be understood that thefollowing compounds are most preferred due to their high level ofantithrombotic activity and low level of toxicity.

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-methoxyethylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-phenethylalanine

The pharmaceutically acceptable salts of the above compounds are ofcourse also included within the scope of this invention.

The above compounds are intended only to illustrate the variety ofstructures which can be used in the process of this invention, and theabove listing is not to be construed as limiting the scope of theinvention.

For the preparation of the compounds of this invention, various methodscan be employed depending upon the particular starting materials and/orintermediates involved. Successful preparation of these compounds ispossible by way of several synthetic routes which are outlined below.

a. Condensation of an L-argininamide with an alkoxynaphthalenesulfonylhalide

This process may be illustrated as follows: ##STR3##

In the above formulas, R₁, R₂, R₃ and R₄ are as defined herein above,and X is halogen.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) is prepared by thecondensation of an L-argininamide (II) with a substantially equimolaramount of an alkoxynaphthalenesulfonyl halide (III), preferably achloride.

The condensation reaction is generally effected in a suitablereaction-inert solvent in the presence of an excess of a base, such asan organic base (triethylamine, pyridine) or a solution of a inorganicbase (sodium hydroxide, potassium carbonate), at a temperature of 0° C.to the boiling temperature of the solvent for a period of 10 minutes to15 hours.

The peferred solvents for the condensation include benzenediethyl ether,diethyl ether-water and dioxane-water.

After the reaction is complete, the formed salt is extracted with water,and the solvent is removed by such standard means as evaporation underreduced pressure to give the N²-alkoxynaphthalenesulfonyl-L-argininamide (I), which can be purified bytrituration or recrystallization from a suitable solvent, such asdiethyl ether-tetrahydrofuran, diethyl ether-methanol andwater-methanol, or may be chromatographed on silica gel.

The L-argininamides (II) starting materials required for thecondensation reaction can be prepared by protecting the guanidino andα-amino groups of the L-arginine via nitration, acetylation,formylation, phthaloylation, trifluoroacetylation,p-methoxybenzyloxycarbonylation, benzoylation, benzyloxycarbonylation,tert-butoxycarbonylation or tritylation and then condensing the formedN^(G) -substituted-N² -substituted-L-arginine with a correspondingsecondary amine by such a conventional process as the acid chloridemethod, azide method, mixed anhydride method, activated ester method orcarbodiimide method, and thereafter selectively removing the protectivegroup.

b. Removal of the N^(G) -substituent from an N^(G) -substituted-N²-alkoxynaphthalenesulfonyl-L-argininamide

This process may be illustrated as follows: ##STR4##

In the above formulas, R₁, R₂, R₃, R₄ and X are as defined herein above;Y" is a protective group for the amino group, such as benzyloxycarbonylor tert-butoxycarbonyl; and Y and Y' are hydrogen and protective groupsfor the guanidino group, such as nitro, tosyl, trityl, oxycarbonyl orthe like. At least one of Y and Y' is a protective group for theguanidino group.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) is prepared byremoving the N^(G) -substituent from an N^(G) -substituted-N²-alkoxynaphthalenesulfonyl-L-argininamide (VIII) by means of acidolysisor hydrogenolysis.

The acidolysis is generally effected by contacting the N^(G)-substituted-N² -alkoxynaphthalenesulfonyl-L-argininamide (VIII) and anexcess of an acid such as hydrogen fluoride, hydrogen chloride, hydrogenbromide or trifluoroacetic acid, without a solvent or in a solvent, suchas an ether (tetrahydrofuran, dioxane), an alcohol (methanol, ethanol)or acetic acid at a temperature of -10° C. to 100° C., and preferably atroom temperature for a period of 30 minutes to 24 hours.

The products are isolated by evaporation of the solvent and the excessacid, or by trituration with a suitable solvent followed by filtrationand drying.

Because of the use of the excess acid, the products are generally theacid addition salts of the N² -alkoxynaphthalenesulfonyl-L-argininamides(I), which can be easily converted to a free amide by neutralization.

The removal of the nitro group and the oxycarbonyl group, e.g.,benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished bythe hydrogenolysis.

The hydrogenolysis is effected in a reaction-inert solvent, e.g.,methanol, ethanol, tetrahydrofuran or dioxane, in the presence of ahydrogen-activating catalyst, e.g., Raney nickel, palladium, orplatinum, in a hydrogen atmosphere at a temperature of 0° C. to theboiling temperature of the solvent for a period of 2 hours to 120 hours.

The hydrogen pressure is not critical, and atmospheric pressure issufficient.

The N² -alkoxynaphthalenesulfonyl-L-argininamides (I) are isolated byfiltration of the catalyst followed by evaporation of the solvent.

The N² -alkoxynaphthalenesulfonyl-L-argininamides can be purified in thesame manner as described above.

The N^(G) -substituted-N² -alkoxynaphthalenesulfonyl-L-argininamides(VIII) starting materials can be prepared by condensing an N^(G)-substituted-N² -substituted-L-arginine (IV) (generally the N²-substituent is a protective group for the amino group, such asbenzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a correspondingsecondary amine (V) via the azide method, mixed anhydride method,activated ester method, carbodiimido method or the like, selectivelyremoving only the N² -substituent of an N^(G) -substituted-N²-substituted-L-argininamide (VI) by means of catalytic hydrogenolysis oracidolysis, and then condensing the thus obtained N^(G)-substituted-L-argininamide (VII) with an alkoxynaphthalenesulfonylhalide (III), preferably a chloride in the presence of a base in asolvent. These reaction conditions are as described above in thecondensation of an L-argininamide with an alkoxynaphthalenesulfonylhalide, and the removal of the N^(G) -substituent from an N^(G)-substituted-N² -alkoxynaphthalenesulfonyl-L-argininamide.

c. Condensation of an N² -alkoxynaphthalenesulfonyl-L-arginyl halidewith an amine

This process may be illustrated as follows: ##STR5## In the aboveformulas, R₁, R₂, R₃, R₄ and X are as defined herein above.

The N² -alkoxynaphthalenesulfonyl-L-arginamide (I) is prepared by thecondensation of an N² -alkoxynaphthalenesulfonyl-L-arginyl halide (IX),preferably a chloride with at least an equimolar amount of a secondaryamine (V).

The condensation reaction can be carried out without an added solvent.However, satisfactory results will be obtained with the use of a solventsuch as basic solvents (dimethylformamide, dimethylacetamide, etc.) orhalogenated solvents (chloroform, dichloromethane, etc.).

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N²-alkoxynaphthalenesulfonyl-L-arginyl halide (IX).

Preferred condensation reaction temperatures are in the range of from-10° C. to room temperature. The reaction time is not critical, butvaries with the secondary amine (V) employed. In general, a period offrom 5 minutes to 10 hours is operable.

The obtained N² -alkoxynaphthalenesulfonyl-L-argininamide can beisolated and purified in the same manner as described above.

The N² -alkoxynaphthalenesulfonyl-L-arginyl halide (IX) startingmaterials required for the condensation reaction can be prepared byreacting an N² -alkoxynaphthalenesulfonyl-L-arginine with at least anequimolar amount of a halogenating agent such as thionyl chloride,phosphorous oxychloride, phosphorus trichloride, phosphorouspentachloride or phosphorus tribromide. The halogenation can be carriedout with or without an added solvent.

The preferred solvents are chlorinated hydrocarbons such as chloroformand dichloromethane, and ethers such as tetrahydrofuran and dioxane.

The amount of the solvent to be used is not critical and may vary fromabout 5 to 100 times the weight of the N²-alkoxynaphthalenesulfonyl-L-arginine. Preferred reaction temperaturesare in the range of -10° C. to room temperature. The reaction time isnot critical, but varies with the halogenating agent and reactiontemperature. In general, a period of 15 minutes to 5 hours is operable.

d. Guanidylation of an N² -alkoxynaphthalenesulfonyl-L-ornithinamide oran acid addition salt thereof

This process may be illustrated as follows: ##STR6## In the aboveformulas, R₁, R₂, R₃ and R₄ are as defined herein above.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) is prepared byguanidylating an N² -alkoxynaphthalenesulfonyl-L-ornithinamide (X) withan ordinary guanidylating agents such as an O-alkylisourea,S-alkylisothiourea, 1-guanyl-3,5-dimethylpyrazole or carbodiimide. Thepreferred guanidylating agents are the O-alkylisourea and theS-alkylisothiourea.

The guanidylation of the N² -alkoxynaphthalenesulfonyl-L-ornithinamide(X) with the O-alkylisourea or S-alkylisothiourea is generally effectedin a solvent in the presence of a base at a temperature of from 0° C. tothe boiling temperature of the solvent for a period of from 30 minutesto 50 hours.

Examples of the preferred base are triethylamine, pyridine, sodiumhydroxide and sodium methoxide.

The base is used in an amount of 0.01 to 0.1 equivalent to the N²-alkoxynaphthalenesulfonyl-L-ornithinamide.

Examples of the preferred solvent are water, water-ethanol andwater-dioxane.

After the reaction is complete, the N²-alkoxynaphthalenesulfonyl-L-argininamide (I) is isolated by evaporationof the solvent followed by removal of the excess base and the formedsalt by a water wash.

It is well recognized in the art that an ester derivative of the N²-alkoxynaphthalenesulfonyl-L-argininamide (I) wherein R₄ is alkyl, canbe prepared from a carboxylic acid derivative of the N²-alkoxynaphthalenesulfonyl-L-argininamide wherein R₄ is hydrogen, by theconventional esterification methods well known to those skilled in theart. It is also well recognized in the art that the carboxylic acidderivative can be prepared from the ester derivative by the conventionalhydrolysis or acidolysis methods. The conditions under whichesterification, hydrolysis or acidolysis would be carried out will beeach apparent to those skilled in the art.

The N² -alkoxynaphthalenesulfonyl-L-argininamide (I) of this inventionforms acid addition salts with any of a variety of inorganic and organicacids. Some of the N² -alkoxynaphthalenesulfonyl-L-argininamidecontaining a free carboxy group, wherein R₄ is hydrogen, forms saltswith any of a variety of inorganic and organic bases. The product of thereactions described above can be isolated in the free form or in theform of salts. In addition, the product can be obtained aspharmaceutically acceptable acid addition salts by reacting one of thefree bases with an acid, such as hydrochloric, hydrobromic, hydroiodic,nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic,tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic acid or the like. In a similarmanner, the product can be obtained as pharmaceutically acceptable saltsby reacting one of the free carboxylic acids with a base, such as sodiumhydroxide, potassium hydroxide, ammonium hydroxide, triethylamine,procaine, dibenzylamine, 1-ephenamine, N,N'-dibenzylethylenediamine,N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in aregeneration of the free amide.

As stated above, the N² -alkoxynaphthalenesulfonyl-L-argininamides, andthe salts thereof of this invention are characterized by highly specificinhibitory activity against thrombin as well as their substantial lackof toxicity, and therefore these compounds are useful in thedetermination of thrombin in blood as diagnostic reagents, and/or forthe medical control or prevention of thrombosis.

The antithrombotic activities of the N²-alkoxynaphthalenesulfonyl-L-argininamide of this invention werecompared with that of a known antithrombotic agent, N²-(p-tolylsulfonyl)-L-arginine methyl ester, by determining thefibrinogen coagulation time. The measurement of the fibrinogencoagulation time was conducted as follows:

An 0.8 ml aliquot of a fibrinogen solution, which had been prepared bydissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied byArmour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solutionin the same buffer, and 0.1 ml of a thrombin solution (5 units/ml)supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutionsin an ice bath. Immediately after mixing, the reaction mixture wastransferred from the ice bath to a bath maintained at 25° C. Coagulationtimes were taken as the period between the time of transference to the25° C. bath and the time of the first appearance of fibrin threads. Inthe cases where no drug samples were added, the coagulation time was50-55 seconds.

The experimental results are summarized in Table 1. The term"concentration required to prolong the coagulation time by a factor oftwo" is the concentration of an active ingredient required to prolongthe normal coagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factorof two for the known antithrombotic agent, N²-(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100 μm.

The inhibitors are shown in Table 1 by indicating R₁, R₂, R₃ and R₄ inthe formula (I) and the addition moiety.

When a solution containing an N²-alkoxynaphthalenesulfonyl-L-argininamide of this invention wasadministered intravenously into animal bodies, the high antithromboticactivity in the circulating blood was maintained for from one to threehours. The halflife for decay of the antithrombotic compounds of thisinvention in circulating blood was shown to be approximately 60 minutes;the physiological conditions of the host animals (rat, rabbit, dog andchimpanzee) were well maintained. The experimental decrease offibrinogen in animals caused by infusion of thrombin was satisfactorilycontrolled by simultaneous infusion of the compounds of this invention.

The acute toxicity values (LD₅₀) determined by intraperitonealadministration of substances of formula (I) in mice (male, 20 g) rangefrom about 1,000 to 10,000 milligrams per kilogram of body weight.Representative LD₅₀ values, for example, for N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylalanine and N²-(4,6-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylmethylalanineare above 1,500 milligrams per kilogram each.

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide andN² -dansyl-N-methyl-N-butyl-L-argininamide are 75 and 70 milligrams perkilogram, respectively.

The therapeutic agents of this invention may be administered alone or incombination with pharmaceutically acceptable carriers, the proportion ofwhich is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard pharmaceuticalpractice. For example, the compounds may be injected parenterally, thatis, intramuscularly, intravenously or subcutaneously. For parenteraladministration, the compounds may be used in the form of sterilesolutions containing other solutes, for example, sufficient saline orglucose to make the solution isotonic. The compounds may be administeredorally in the form of tablets, capsules, or granules containing suitableexcipients such as starch, lactose, white sugar and the like. Thecompounds may be administered sublingually in the form of troches orlozenges in which each active ingredient is mixed with sugar or cornsyrups, flavoring agents and dyes, and then dehydrated sufficiently tomake the mixture suitable for pressing into solid form. The compoundsmay be administered orally in the form of solutions which may containcoloring and flavoring agents.

Physicians will determine the dosage of the present therapeutic agentswhich will be most suitable, and dosages vary with the mode ofadministration and the particular compound chosen. In addition, thedosage will vary with the particular patient under treatment.

When the composition is administered orally, a larger quantity of theactive agent will be required to produce the same effect as caused witha smaller quantity given parenterally. The therapeutic dosage isgenerally 10-50 mg/kg of active ingredient parenterally, 10-500 mg/kgorally per day.

Having generally described the invention, a more complete understandingcan be obtained by reference to certain specific examples, which areincluded for purposes of illustration only and are not intended to belimiting unless otherwise specified.

EXAMPLE 1

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-phenethylalanine

To a solution of 3.00 g of N^(G) -nitro-N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-phenethylalaninebenzyl ester in 50 ml of acetic acid was added 0.5 g of palladium-blackand then the mixture was shaken in a hydrogen atmosphere for 100 hoursat room temperature. At the end of this period, the ethanol solution wasfiltered to remove the catalyst and evaporated to dryness. The residuewas washed several times with dry diethyl ether and chromatographed on80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H⁺ form,manufactured by Mitsubishi Chemical Industries Limited) packed in water,washed with water, and eluted with 3% ammonium hydroxide solution. Thefraction eluted from 3% ammonium hydroxide was evaporated to dryness togive 1.64 g (67%) of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-phenethylalanine asan amorphous solid.

    I.R. (KBr): 3,360, 3,160, 1,600 cm.sup.-1

Analysis -- Calcd. for C₂₉ H₃₇ N₅ O₇ S (percent): C, 58.08; H, 6.22; N,11.68

    found (percent): C, 57.84; H, 6.13; N, 11.46

example 2

n² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalanine

A. N-benzylalanine tert-butyl ester

To 65.0 g of benzylamine in 100 ml of benzene was added with stirring25.0 g of tert-butyl 2-chloropropionate over a period of 30 minutes,while maintaining the temperature at 30°-70° C. The reaction mixture washeld at 70° C. for an additional one hour. At the end of this period,the reaction mixture was taken up in 70 ml of 2N NaOH solution and 80 mlof benzene, transferred into a separatory funnel and well shaken. Thebenzene solution was separated, washed with water, dried over anhydroussodium sulfate and filtered. After evaporation of benzene, the residuewas distilled under reduced pressure to give 33.2 g (90.0 percent) ofN-benzylalanine tert-butyl ester, B.P. 164° C./14 mmHg.

Analysis -- Calcd. for C₁₄ H₂₁ NO₂ (percent): C, 71.45; H, 7.00; N, 5.95

     found (percent): C, 71.38; H, 6.98; N, 5.96

b. n² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloridehydrochloride

A suspension of 2.00 g of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine in 20 ml of thionylchloride was stirred for 2 hours at room temperature. Addition of colddry diethyl ether results in a precipitate which was collected byfiltration and washed several times with dry diethyl ether to give N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride.

C. N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalaninetert-butyl ester

To a stirred solution of 4.42 g of N-benzylalanine tert-butyl ester in20 ml of chloroform was carefully added N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochlorideobtained above. The reaction mixture was allowed to stand at roomtemperature for 1 hour. At the end of this period, the reaction mixturewas washed twice with 20 ml of saturated sodium chloride solution andevaporated to dryness to give 2.50 g (83 percent) of N²-(6,7-dimethoxynaphthalenesulfonyl)-L-arginyl-N-benzylalanine tert-butylester in the form of a powder.

    The flavianate; M.P. 168°-172° C. (dec.)

     I.R. (KBr): 3,380, 3,180, 1,740 cm.sup.-1

Analysis -- Calcd. for C₃₂ H₄₃ O₇ N₅ S.C₁₀ H₆ O₈ N₂ S (percent): C,52.77; H, 5.17; N, 10.26

     found (percent): C, 52.54; H, 4.98; N, 10.21

d. n² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalanine

To a solution of 2.00 g of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalaninetert-butyl ester in 20 ml of chloroform was added 30 ml oftrifluoroacetic acid. The reaction mixture was stirred for 5 hours atroom temperature. At the end of this period, the reaction mixture wasevaporated to dryness. The residue was washed several times with drydiethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ionexchange resin (200-300 mesh, H⁺ form, manufactured by MitsubishiChemical Industries Limited) packed in water, washed with water andeluted with 3% ammonium hydroxide solution.

The fraction eluted from 3% ammonium hydroxide solution was evaporatedto dryness to give 1.26 g (69 percent) of N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalanine as anamorphous solid.

     I.R. (KBr): 3,350-3,160 (broad), 1,600 cm.sup.-1

Analysis -- Calcd. for C₂₈ H₃₅ N₅ O₇ S (percent): C, 57.42; H, 6.02; N,11.96

     found (percent): C, 57.35; H, 5,84; N, 12.00

various other N² -alkoxynaphthalenesulfonyl-L-arginamides or acidaddition salts thereof were synthesized in accordance with the procedureof the above examples, and the test results are summarized in Table 1.

      COMPOUND      ##STR7##      ConcentrationRequired ToProlong TheCoagulationTime By AFactor Of Two     Prepara-tionProcess m.p. Elementary AnalysisUpper: CalculatedLower:     Found I.R.(KBr) SAMPLE     Addition        NUMBER R.sub.1 R.sub.2     R.sub.3 R.sub.4 Moiety (μM) (Ex.No.) (°      C) C H N (cm.sup.-1)                  1      ##STR8##      (CH.sub.2).sub.3      CH.sub.3 CH.sub.3 C(CH.sub.3).sub.3     ##STR9##       2 165-170(dec) 50.8150.68 5.585.43 10.6410.31 3,3803,2001,740 2      ##STR10##      (CH.sub.2).sub.3 CH.sub.3 " H   2 powder 54.4354.70 6.766.71 12.7012.35     3,4001,590 3      ##STR11##     (CH.sub.2)CH.sub.3 " C(CH.sub.3).sub.3      ##STR12##       2 164-166 51.3351.60 5.715.38 10.4810.25 3,3603,2001,735 4      ##STR13##      (CH.sub.2).sub.4 CH.sub.3 " H  2.0 2 powder 55.2155.00 6.956.30     12.3812.40 3,400-3,200(Broad)1,570 5      ##STR14##      ##STR15##      " C(CH.sub.3).sub.3      ##STR16##       2 168-172 52.7752.54 5.174.98 10.2610.21 3,3803,180 1,740

      COMPOUND      ##STR17##      ConcentrationRequired To Prolong TheCoagulationTime By AFactor Of Two     Prepara-tionProcess m.p. Elementary AnalysisUpper: CalculatedLower:     Found I.R.(KBr) SAMPLE     Addition        NUMBER R.sub.1 R.sub.2     R.sub.3 R.sub.4 Moiety (μM) (Ex.No.) (°      C) C H N (cm.sup.-1)                  6      ##STR18##      ##STR19##      3 H  2.5 2 powder 57.4257.35 6.025.84 11.9612.00 3,350-3,160(Broad)1,600      7      ##STR20##      ##STR21##      " C(CH.sub.3).sub.3      ##STR22##       2 130-135 53.2553.08 5.305.29 10.1110.29 3,4003,2001,730 8      ##STR23##      ##STR24##      CH.sub.3 H  1.5 1 powder 58.0857.84 6.226.13 11.6811.46 3,3603,1601,600     9      ##STR25##      ##STR26##      " C(CH.sub.3).sub.3      ##STR27##       2 158-163 (dec) 51.9551.80 5.645.38 10.3410.30 3,3603,2001,740 10      ##STR28##      ##STR29##      " H   2 powder 56.1455.98 6.816.79 12.1312.35 3,380-3,200(Broad)1,625

      COMPOUND      ##STR30##      ConcentrationRequired ToProlong TheCoagulationTime By AFactor Of Two     Prepara-tionProcess m.p. Elementary AnalysisUpper: CalculatedLower:     Found I.R.(KBr) SAMPLE     Addition        NUMBER R.sub.1 R.sub.2     R.sub.3 R.sub.4 Moiety (μM) (Ex. No.) (°      C) C H N (cm.sup.-1)                 11      ##STR31##      ##STR32##      " C(CH.sub.3).sub.3      ##STR33##       2 160-163(dec) 52.4452.39 5.765.58 10.1910.00 3,4003,2001,740 12      ##STR34##      ##STR35##      " H  4.5 2 powder 56.8456.72 6.996.80 11.8411.76 3,380-3,250(Broad)1,595      13      ##STR36##      (CH.sub.2).sub.2      CH.sub.3 " C(CH.sub.3).sub.3     ##STR37##       2 160-165(dec) 50.6250.39 5.405.28 11.1711.15 3,4003,2101,740 14      ##STR38##      (CH.sub.2).sub.2 CH.sub.3 " H   1 powder 54.4354.27 6.556.28 13.8013.59     3,2801,590 15      ##STR39##      CH.sub.2 CH.sub.2 OCH.sub.3 " H  5 2 powder 52.0751.89 6.376.39     12.6512.51 3,3603,2001,600

The following compounds are prepared in a similar manner:

N²-(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethoxyethyl)alanine

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylalanine

N² (7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-pentylalanine

N² -(5-methoxy-1-naphthalenesulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-isobutylalanine

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalanine

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(3-phenylpropyl)alanine

N² -(5-methoxy-1-naphthalenesulfonyl)-L-arginyl-N-benzylalanine

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylalanine

N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylmethylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylbutyrine

N²-(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methoxyethyl)norvaline

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylleucine

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-cyclohexylnorleucine

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylisoleucine

N² -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-pentylbutyrine

N² -(6,7-diethoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylalanine

N² -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-cycloheptylalanine

EXAMPLE 3

Tablets suitable for oral administration

Tablets containing the ingredients indicated below may be prepared byconventional techniques.

    ______________________________________                                                                 Amount per                                           Ingredient               tablet (mg)                                          ______________________________________                                        N.sup.2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-                                                        250                                                  L-arginyl-N-(2-methoxyethylal)anine                                           Lactose                  140                                                  Corn starch               35                                                  Talcum                    20                                                  Magnesium stearate        5                                                   Total                    450 mg                                               ______________________________________                                    

EXAMPLE 4

Capsules for oral administration

Capsules of the below were made up by thoroughly mixing together batchesof the ingredients and filling hard gelatin capsules with the mixture.

    ______________________________________                                                                 Amount per                                                                    capsule                                              Ingredient               (mg)                                                 ______________________________________                                        N.sup.2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-                                                        250                                                  L-arginyl-N-(2-methoxyethyl)alanine                                           Lactose                  250                                                  Total                    500 mg                                               ______________________________________                                    

EXAMPLE 5

Sterile solution for infusion

The following ingredients are dissolved in water for intravenousperfusion and the resulting solution is then sterilized.

    ______________________________________                                                                 Amount                                               Ingredients              (g)                                                  ______________________________________                                        N.sup.2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-                                                        25                                                   L-arginyl-N-(2-methoxyethyl)alanine                                           Buffer system            As desired                                           Glucose                  25                                                   Distilled water          500                                                  ______________________________________                                    

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit of the invention as setforth herein.

WHAT IS CLAIMED AS NEW AND INTENDED TO BE COVERED BY LETTERS PATENTIS:
 1. N² -alkoxynaphthalenesulfonyl-L-argininamides having the formula(I): ##STR40## and the pharmaceutically acceptable salts thereof,wherein R₁ is naphthyl substituted with at least one C₁ -C₅ alkoxy; R₂is selected from the group consisting of C₂ -C₁₀ alkyl, C₂ -C₁₀alkoxyalkyl, C₂ -C₁₀ alkylthioalkyl, C₇ -C₁₅ aralkyl, C₃ -C₁₀ cycloalkyland C₄ -C₁₀ cycloalkylalkyl; R₃ is C₁ -C₅ alkyl; and R₄ is selected fromthe group consisting of hydrogen, C₁ -C₁₀ alkyl, C₇ -C₁₂ aralkyl and C₆-C₁₀ aryl.
 2. The compound of claim 1, wherein R₁ is naphthylsubstituted with one or two C₁ -C₃ alkoxy; R₂ is selected from the groupconsisting of C₂ -C₆ alkyl, C₂ -C₆ alkoxyalkyl, C₂ -C₆ alkylthioalkyl,C₇ -C₁₀ aralkyl, C₃ -C₁₀ cycloalkyl and C₄ -C₁₀ cycloalkylalkyl; R₃ isC₁ -C₅ alkyl; and R₄ is selected from the group consisting of hydrogen,C₁ -C₆ alkyl, phenyl and C₇ -C₁₀ aralkyl.
 3. The compound of claim 2,wherein R₁ is selected from the group consisting of5-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl,4,6-dimethoxy-2-naphthyl, 7-methoxy-2-naphthyl,4,6-dimethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl and6,7-diethoxy-2-naphthyl; R₂ is selected from the group consisting ofpropyl, butyl, isobutyl, pentyl, hexyl, octyl, 2-methoxyethyl,2-ethoxyethyl, 3-methoxypropyl, 2-methylthioethyl, 2-ethylthioethyl,3-methylthiopropyl, benzyl, phenethyl, 3-phenylpropyl, cyclopropyl,cyclohexyl, cycloheptyl and cyclohexylmethyl; R₃ is methyl or isopropyl;and R₄ is hydrogen, ethyl or tert-butyl.
 4. A compound of claim 3, whichis N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-methoxyethyl)alanine5. A compound of claim 3, which is N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-butylalanine.
 6. Acompound of claim 3, which is N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylalanine.
 7. Acompound of claim 3, which is N²-(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-phenethylalanine. 8.A method of inhibiting activity and suppressing activation of thrombinin vivo, which comprises administering to a patient a pharmaceuticallyeffective amount of an N² -alkoxynaphthalenesulfonyl-L-argininamidehaving the formula (I): ##STR41## or the pharmaceutically acceptablesalts thereof, wherein R₁ is naphthyl substituted with at least one C₁-C₅ alkoxy; R₂ is selected from the group consisting of C₂ -C₁₀ alkyl,C₂ -C₁₀ alkoxyalkyl, C₂ -C₁₀ alkylthioalkyl, C₇ -C₁₅ aralkyl, C₃ -C₁₀cycloalkyl and C₄ -C₁₀ cycloalkylalkyl; R₃ is C₁ -C₅ alkyl; and R₄ isselected from the group consisting of hydrogen, C₁ -C₁₀ alkyl, C₇ -C₁₂aralkyl and C₆ -C₁₀ aryl.